The recent availability of a genetic test (homozygosity for the C282Y mutation in the HFE gene) for the diagnosis of hereditary hemochromatosis (HH) has focused renewed attention on this relatively common disorder. However, phlebotomy therapy in HH remains hampered by lack of simple, physiologic laboratory monitoring guides. In addition, phlebotomy therapy has been perceived as wasteful because the blood obtained is not used for allogeneic transfusion, although many HH subjects meet standards for allogeneic blood donation. Recent regulatory changes now allow increased flexibility in establishing policies for transfusion of blood obtained from HH subjects. We developed a protocol for use of the red cell mean corpuscular volume (MCV), a precisely measured indicator of erythopoietic iron availability, as a simple, physiologically based target to guide the pace of induction and maintenance phlebotomy for HH. We also developed a program to use blood therapeutically withdrawn from HH subjects for allogeneic transfusion. To enable the operational aspects of using HH donor blood for transfusion, a customized multi-user database program was developed as a Microsoft Access application to maintain and analyze lab data, generate a schedule of phlebotomy intervals and appointment dates, and notify staff when pre-set therapeutic endpoints were reached. We enrolled 113 patients with HH in the first two years of this protocol. Induction phlebotomy to achieve iron depletion was performed every 1 to 4 weeks, depending on subject weight and initial ferritin levels, and continued until the MCV decreased by 3% below pretreatment baseline. A fingerstick hemoglobin (HGB) greater than 12.5 g/dL was used as the threshold for performing phlebotomy. Maintenance phlebotomy was targeted to maintain the red cell MCV at 3% below baseline. Median pre-treatment values in the first 53 previously untreated patients included ferritin 1035 (range 26-4938) ng/mL, transferrin saturation (TS) 72 (29-106)%, and MCV 95.6 (84-105) cubic microns. Mean ferritin was 27 ng/mL, TS was 22%, and HGB was 13.7 g/dL at the point of transition from induction to maintenance therapy, as defined by the MCV guide. A mean of 25 induction bleeds were performed in HFE homozygotes and 14 bleeds in C282Y/H63D double heterozygotes until iron-depletion was achieved. Mean nadir HGB of 13.3 g/dL occurred 2 (0-4) weeks after the transition to maintenance therapy, and mean nadir MCV of 87.4 occurred 6-8 weeks after the transition. The mean iron removal necessary to maintain a stable ferritin, MCV and TS during maintenance therapy in 22 C282Y homozygotes was 50 ug/kg/day, was highly correlated with body weight, and was significantly higher in the C282Y homozygotes than in five C282Y/H63D double heterozygotes, 33 ug/kg/day. Women and older subjects tolerated initial induction phlebotomy better at two, rather than one week intervals. These data correspond to a stable maintenance interval of every 9-10 weeks for C282Y/C282Y homozygotes, and every 11 to 12 weeks for compound heterozygotes of similar size using 500 mL whole blood phlebotomy and a targeted maintenance HGB of 14 g/dL. 33 of 55 (60%) of HH subjects had arthritis on entry, but there was no definite improvement in joint complaints with progressive iron depletion. Occurrence of arthritis was highly correlated with higher iron burden at presentation and with C282Y homozygosity. 85 (75%) of the HH subjects met donor eligibility criteria. The contribution of red cell units derived from HH subjects to total allogeneic inventory in our center has progressively increased to, and now stblized at, 9% of all allogeneic red cell units collected at our center. Positive viral markers were found in 4 HH subjects, all of whom admitted deferrable risk prior to testing. Subjects expressed great satisfaction in knowing their blood was made available to others rather than discarded. Use of the red cell MCV provides an inexpensive, simple, and individualized parameter that is widely available and suitable for use to achieve optimal phlebotomy therapy. Our data indicate that serial MCV changes reliably indicate iron depletion, and can be used to avoid symptomatic anemia at the transition to maintenance phlebotomy. HH subjects can safely augment the allogeneic blood supply, leading to improvements in allogeneic inventory, in HH patient care, and in benefit to the community. Our data argue strongly for a comprehensive movement of HH phlebotomy care into the blood center. Universal genetic screening for HH, and use of HH donor blood for transfusion (from otherwise eligible donors) would increase the number of blood units collected in the U.S. by 12% and alleviate periodic critical blood shortages.